Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adrenomedullin (AM), a potent vasodilatory peptide, has anti-proliferative and pro-apoptotic effects in rat mesangial cells (RMCs). We have previously demonstrated that AM modulates activities of the members of MAPK family in RMCs. Because activation of MAPKs has been reported to induce AP-1 expression in other cell systems, the major aim of the present study was to examine the effects and mechanisms of AM on AP-1 member mRNA expression, in RMCs. AM produced a concentration- and time-dependent increase in c-fos and jun-B mRNA expression without observable effects on fos-B and c-jun. Associated with this change, AM increased the AP-1 DNA binding activity. RMCs transiently transfected with a luciferase fusion gene driven by an AP-1 cis-element demonstrate a concentration- and time-dependent increase in luciferase activity suggesting that AM increases AP-1-mediated gene transcription in these cultured cells. Both an AM-induced increase in AP-1 mRNA expression and AP-1 luciferase activities were inhibited by H89 (protein kinase-A inhibitor) and SB203580 (p38 MAPK inhibitor). These results indicate a likely role for the members of AP-1 family in AM-mediated biological responses in rat mesangial cells and a role for cAMP activation and subsequent activation of p38 MAPK in AM-induced AP-1 activity.
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PMID:Adrenomedullin increases AP-1 expression in rat mesangial cells via activation of protein kinase-A and p38 MAPK. 1463 Nov 43

Adrenomedullin (AM), a potent vasodilatory peptide has beneficial effects in the kidney IN VIVO. The major aim of the present study was to determine the presence of AM receptor and the biological outcomes of AM on kidney interstitial fibroblasts in culture. Utilizing RT-PCR we found that NRK-49F cells express calcitonin receptor like receptor (CRLR) and receptor activity modifying protein 2 (RAMP2) but not RAMP3. Treatment of these cells with AM resulted in a concentration-dependent increase in cAMP activation. The activation of adenylate cyclase system was enhanced by over-expression of CRLR, RAMP2 and RAMP3. Furthermore, AM-stimulated adenylate cyclase activity was inhibited by AM-[22-52] the AM receptor antagonist. AM also caused a PKA-dependent increase in CRE-luciferase activity. To test the biological consequences of AM treatment and the signaling pathways mediating them, we examined the effect of AM on proliferation of NRK-49F cells and the desensitization of AM receptor. AM caused a significant decrease in proliferation that was AM-receptor mediated but was PKA independent. In addition, AM also caused desensitization of cAMP response within a few minutes of treatment. This effect of AM was also not mediated via cAMP pathway as forskolin failed to desensitize AM receptor, and a PKA-inhibitor did not inhibit the desensitization. Taken together these results demonstrate that NRK-49F cells express functional AM receptor that when activated by AM results in a significant reduction of cell proliferation. Although cAMP activation by AM, as in other systems, is also observed in NRK-49F cells, PKA-independent pathways lead to some of the biological responses observed in these cells.
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PMID:Regulation of adrenomedullin signaling in kidney interstitial fibroblasts. 1463 Nov 46

Adrenomedullin (AM) is a potent vasoactive peptide and plays an important role in cardiovascular function. In this study, we delivered the AM gene locally into the heart, using a catheter-based technique to investigate the signaling mechanism mediated by AM in protection against cardiomyocyte apoptosis induced by acute ischemia/reperfusion. After adenovirus-mediated gene delivery, highly efficient and specific expression of luciferase, green fluorescent protein, or recombinant human AM was identified in the left ventricle. Delivery of the AM gene 5 days before ischemia/reperfusion attenuated myocardial apoptosis identified by in situ dUTP nick-end labeling and DNA laddering, and the effect was blocked by the AM antagonist human calcitonin gene-related peptide (CGRP 8 to 37). AM gene transfer increased phosphorylation of Akt and glycogen synthase kinase (GSK-3beta) but reduced GSK-3beta and caspase-3 activities in the heart. The effects of AM on GSK-3beta and caspase-3 activities were blocked by CGRP (8-37) and by adenovirus containing dominant-negative Akt (DN-Akt). Furthermore, in cultured cardiomyocytes, AM also attenuated apoptosis induced by hypoxia/reoxygenation, which was accompanied by increased phospho-GSK-3beta but reduced GSK-3 and caspase-3 activities. GSK-3 and caspase-3 activities were both blocked by Ad.DN-Akt and lithium, whereas only caspase-3 was inhibited by its inhibitor Z-VAD. The effects of AM on anti-apoptosis and promoting cell viability were blocked by DN-Akt but not by constitutively active Akt, lithium, or Z-VAD. These results indicate that AM protects against cardiomyocyte apoptosis induced by ischemia/reperfusion injury through the Akt-GSK-caspase signaling pathway.
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PMID:Adrenomedullin protects against myocardial apoptosis after ischemia/reperfusion through activation of Akt-GSK signaling. 1466 48

Adrenomedullin (AM), a potent vasodilator peptide, has recently been suggested to function as an endogenous antioxidant. However, its potential site of action at the cellular level has not been clarified. The present study was undertaken to investigate whether AM directly inhibits intracellular reactive oxygen species (ROS) generation and redox-sensitive gene expression stimulated by angiotensin (Ang) II in rat aortic endothelial cells (ECs). Ang II (10(-7) mol/l) significantly increased intracellular ROS levels in ECs as measured by dichlorofluorescein (DCF) fluorescence. AM inhibited Ang II-stimulated ROS generation in a dose-dependent manner and this effect was abolished by a superoxide radical scavenger, NAD(P)H oxidase inhibitor, and a protein kinase A (PKA) inhibitor, and mimicked by a cell-permeable cAMP analog. A real-time reverse transcription-polymerase chain reaction (RT-PCR) study showed that Ang II significantly upregulated a set of redox-sensitive genes (ICAM-1, VCAM-1, PAI-1, tissue factor, MCP-1, osteopontin), and these effects were blocked by an antioxidant, N-acetyl cysteine (NAC). AM similarly and dose-dependently inhibited the Ang II-induced upregulation of the entire set of these genes via a receptor-mediated and PKA-dependent pathway, and the degrees of inhibition were similar to those by NAC. In conclusion, the present study demonstrated that AM potently blocked the Ang II-stimulated intracellular ROS generation from NAD(P)H oxidase and the subsequent redox-sensitive gene expression via a cAMP-dependent mechanism in ECs, suggesting that AM has vasculoprotective effects against pro-oxidant stimuli.
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PMID:Adrenomedullin inhibits angiotensin II-induced oxidative stress and gene expression in rat endothelial cells. 1602 44

Adrenomedullin (ADM) acts as an autocrine or a paracrine factor in the regulation of cardiac function. The intracellular mechanisms involved in the direct effect of ADM on adult rat ventricular myocytes (ARVMs) are still to be elucidated. In ARVMs from normal rats, ADM produced an initial (< 30 min) increase in cell shortening and Ca2+ transients and a marked decrease in both on prolonged incubation (> 1 h). Both effects were sensitive to ADM antagonist ADM-(22-52). Treatment with SQ-22536, an inhibitor of adenylate cyclase, blocked the positive inotropic effect of ADM and potentiated its negative inotropic effect. The negative inotropic effect was sensitive to inhibition by pertussis toxin (PTX), an inhibitor of Gi proteins and KT-5720, an inhibitor of PKA. The observations suggest a switch from Gs-coupled to PTX-sensitive, PKA-dependent Gi coupling by ADM in ARVMs. The ADM-mediated Gi-signaling system involves cAMP-dependent pathways because SQ-22536 further increased the negative inotropic actions of ADM. Also, because ADM is overproduced by ARVMs in our rat model of septic shock, ARVMs from LPS-treated rats were subjected to treatment with ADM-(22-52) and PTX. The decrease in cell shortening and Ca2+ transients in LPS-treated ARVMs could be reversed back with ADM-(22-52) and PTX. This indicates that ADM plays a role in mediating the negative inotropic effect in LPS-treated ARVM through the activation of Gi signaling. This study delineates the intracellular pathways involved in ADM-mediated direct inotropic effects on ARVMs and also suggests a role of ADM in sepsis.
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PMID:Gs and Gi coupling of adrenomedullin in adult rat ventricular myocytes. 1632 20

The mechanism of adrenomedullin-induced prolactin release was investigated in prolactin-secreting human pituitary adenoma cells by intracellular calcium measurement and static incubation study. Adrenomedullin stimulated prolactin release in a concentration-dependent manner. The stimulation was dependent on extracellular sodium and voltage-gated calcium channels. PKA inhibitor attenuated adrenomedullin-induced prolactin release. The mechanism of adrenomedullin action was studied by fura 2-based intracellular calcium measurement. Adrenomedullin increased intracellular calcium concentration in these cells. The increase was dependent on extracellular sodium and voltage-gated calcium channels. PKA inhibitor attenuated the calcium response. These data indicate that adrenomedullin stimulates prolactin release by modulating calcium influx through voltage-gated calcium channels dependently on extracellular sodium. Mechanisms involving sodium-influx mediated depolarization may play a role in the stimulatory action.
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PMID:Mechanism of adrenomedullin-induced prolactin release from human prolactin-releasing adenoma cells. 1641 Jun 71

The mechanisms of relaxation of adrenomedullin were investigated in isolated mesenteric artery from pregnant rats. Adrenomedullin (1 nM-0.3 microM) produced concentration-dependent relaxation of endothelium-denuded mesenteric artery rings precontracted with norepinephrine at a concentration required to produce 70% of maximal response (ED70). The concentration-response curve of adrenomedullin was shifted to the right by adrenomedullin receptor antagonist adrenomedullin(22-52) (10 microM) or calcitonin gene-related peptide(8-37) (1 microM). Inhibition of adenylate cyclase by 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ22536) (10 microM) or protein kinase A [Rp-cyclic adenosine monophosphorothioate (Rp-cAMP); 10 microM] reduced the adrenomedullin-induced relaxation to the same magnitude. Adrenomedullin increased the intracellular cAMP level from 0.38 +/- 0.07 to 2.00 +/- 0.47 pmol/mg tissues, which was completely inhibited by adrenomedullin(22-52) (100 microM). Extracellular high potassium (80 mM), which inactivates the potassium channels, reduced the adrenomedullin-induced relaxation. Blockade of ATP-sensitive, voltage-gated, or inward rectifier potassium channels did not affect the adrenomedullin-induced relaxation. Blockade of calcium-activated K+ channels (KCa) by tetraethylammonium (1 mM) or iberiotoxin (100 nM) inhibited the adrenomedullin-induced relaxation, whereas there was no additional inhibition by SQ22536 or Rp-cAMP when KCa channels were already inhibited. In conclusion, this study provides evidence that cAMP-dependent protein kinase A and KCa channels seem to mediate as the cellular pathways in the adrenomedullin-induced endothelium-independent relaxation of mesenteric artery from pregnant rats.
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PMID:Endothelium-independent relaxation by adrenomedullin in pregnant rat mesenteric artery: role of cAMP-dependent protein kinase A and calcium-activated potassium channels. 1655 34

Adrenomedullin (ADM) in the brain plays important roles in the maintenance of homeostasis. Although in vivo evidence has suggested that nitric oxide (NO) mediates ADM's effects in the brain, mechanisms for ADM stimulation of NO production in neurons have not been identified. In the present study, primary hypothalamic neurons were used to characterize ADM-induced NO production and to study the underlying mechanisms. Using Calcium Orange/4-amino-5-methylamino-2',7'-difluorofluorescein fluorescence live cell imaging, we found that ADM (1 or 10 nM, 5 min) significantly elevated [Ca(2+)](i) and NO production in a concentration-dependent manner. Ca(2+) and NO responses induced by 10 nM ADM were abolished by pretreatment with 50 microM 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA-AM), an intracellular Ca(2+) chelator, or protein kinase A (PKA) inhibitors 5 microM N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride (H-89) and 50 microM Rp-cAMP. Furthermore, the ADM-induced NO production was significantly attenuated by a protein phosphatase 1/2A inhibitor, okadaic acid (OA; 0.1 microM), or calcineurin inhibitors, tacrolimus (FK506) (1 microM) and cyclosporin A (CsA; 0.1 microM). Using Western blotting, we found that ADM significantly decreased phosphorylation of neuronal nitric-oxide synthase (nNOS) at serine 847. This dephosphorylation was inhibited by 0.1 microM OA, 1 microM FK506, 0.1 microM CsA, or 5 microM H-89, and attenuated by 50 microM BAPTA-AM. These results suggest that, in hypothalamic neurons, ADM elevates [Ca(2+)](i) via PKA-associated mechanisms. The PKA/Ca(2+) cascade leads to protein phosphatase (PP) 1/PP2A- and calcineurin-mediated dephosphorylation of nNOS. We hypothesize that the Ca(2+) increase and nNOS dephosphorylation contribute to activation of nNOS and production of NO in hypothalamic neurons.
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PMID:Adrenomedullin stimulates nitric oxide production from primary rat hypothalamic neurons: roles of calcium and phosphatases. 1744 68

Adrenomedullin (ADM) is an endogenous peptide with favorable hemodynamic effects in vivo. In this study, we characterized the direct functional effects of ADM in isolated preparations from human atria and ventricles. In electrically stimulated human nonfailing right atrial trabeculae, ADM (0.0001-1 micromol/l) increased force of contraction in a concentration-dependent manner, with a maximal increase by 35 +/- 8% (at 1 micromol/l; P < 0.05). The positive inotropic effect was accompanied by a disproportionate increase in calcium transients assessed by aequorin light emission [by 76 +/- 20%; force/light ratio (DeltaF/DeltaL) 0.58 +/- 0.15]. In contrast, elevation of extracellular calcium (from 2.5 to 3.2 mmol/l) proportionally increased force and aequorin light emission (DeltaF/DeltaL 1.0 +/- 0.1; P < 0.05 vs. ADM). Consistent with a cAMP-dependent mechanism, ADM (1 micromol/l) increased atrial cAMP levels by 90 +/- 12%, and its inotropic effects could be blocked by the protein kinase A (PKA) inhibitor H-89. ADM also exerted positive inotropic effects in failing atrial myocardium and in nonfailing and failing ventricular myocardium. The inotropic response was significantly weaker in ventricular vs. atrial myocardium and in failing vs. nonfailing myocardium. In conclusion, ADM exerts Ca(2+)-dependent positive inotropic effects in human atrial and less-pronounced effects in ventricular myocardium. The inotropic effects are related to increased cAMP levels and stimulation of PKA. In heart failure, the responsiveness to ADM is reduced in atria and ventricles.
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PMID:Atrial myocardium is the predominant inotropic target of adrenomedullin in the human heart. 1776 67

Adrenomedullin (ADM) is upregulated in cardiac tissue under various pathophysiological conditions, particularly in septic shock. The intracellular mechanisms involved in the effect of ADM on adult rat ventricular myocytes are still to be elucidated. Ventricular myocytes were isolated from adult rats 4 h after an intraperitoneal injection of lipopolysaccharide (LPS, 10 mg/kg). Membrane potential and L-type calcium current (I(Ca,L)) were determined using whole cell patch-clamp methods. APD in LPS group was significantly shorter than control values (time to 50% repolarization: LPS, 169 +/- 2 ms; control, 257 +/- 2 ms, P < 0.05; time to 90% repolarization: LPS, 220 +/- 2 ms; control, 305 +/- 2 ms, P < 0.05). I(Ca,L) density was significantly reduced in myocytes from the LPS group (-3.2 +/- 0.8 pA/pF) compared with that of control myocytes (-6.7 +/- 0.3 pA/pF, P < 0.05). The ADM antagonist ADM-(22-52) reversed the shortened APD and abolished the reduction of I(Ca,L) in shock myocytes. In myocytes from control rats, incubating with ADM for 1 h induced a marked decrease in peak I(Ca,L) density. This effect was reversed by ADM-(22-52). The G(i) protein inhibitor, pertussis toxin (PTX), the protein kinase A (PKA) inhibitor, KT-5720, and the specific cyclooxygenase 2 (COX-2) inhibitor, nimesulide, reversed the LPS-induced reduction in peak I(Ca,L). The results suggest a COX-2-involved PKA-dependent switch from G(s) coupled to PTX-sensitive G(i) coupling by ADM in adult rat ventricular myocytes. The present study delineates the intracellular pathways involved in ADM-mediated effects on I(Ca,L) in adult rat ventricular myocytes and also suggests a role of ADM in sepsis.
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PMID:The effect of adrenomedullin on the L-type calcium current in myocytes from septic shock rats: signaling pathway. 1776 82


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